S. Umadevi et al, Indo American Journal of Pharmaceutical Research, 2012:2(8) ISSN NO: 2231-6876

Indo American Journal of Pharmaceutical Research. 2012:2(8)

INDO AMERICAN Journal home page: JOURNAL OF http://www.iajpr.com/index.php/en/ PHARMACEUTICAL RESEARCH

A review;Vesicular delivery-an novel approach

S. Umadevi*, K. Sasidharan, K. Nithyapriya, R.Venkatanarayanan Department of Pharmaceutics, RVS College of Pharmaceutical Sciences, Sulur, Coimbatore-641402. India

ARTICLE INFO ABSTRACT Article history Novel drug delivery system aims to provide some control in temporal Received 25 July 2012 or spatial nature of the drug release in the body. In recent years, Available online 30 July 2012 vesicle have been the vehicle of choice in drug delivery for targeting and controlled release and it can solve the problems of drug solubility, instability and rapid degradation. Vesicular drug delivery Keywords reduces cost of the therapy and can incorporate both the hydrophilic Vesicular system, and lipophilic . Nowadays, a number of vesicular drug delivery bioavailability, system such as , pharmacosomes, ethosomes, depot, controlled transferosomes etc. was developed. This article reviews different release. aspects of this vesicular drug delivery system including their preparation, characterization, advantages and their applications in the drug delivery.

Corresponding author

Department of pharmaceutics, Faculty of pharmacy,RVS College of Pharmaceutical Sciences, Sulur, Coimbatore, Pin – 641402, Tamilnadu, India. Email ID:[email protected] Phone No:+91 9444132145

Please cite this article in press as: S. Umadevi, A review;Vesicular drug delivery-an novel approach . Indo American Journal of Pharm Research. 2012:2(8).

833 S. Umadevi et al, Indo American Journal of Pharmaceutical Research, 2012:2(8) ISSN NO: 2231-6876

INTRODUCTION A number of technical advancement has been recently made in developing new techniques for drug delivery. These techniques are capable of regulating the rate of drug delivery, sustaining the duration of therapeutic action or targeting the delivery of drug to a tissue. This advancement has already leads to development of several novel drug delivery systems. At present, no available drug delivery system behaves ideally, but many attempts have been made to achieve them through various novel approaches in drug delivery. The main aim of novel drug delivery system is to provide some control of drug release in the body, which is either of temporal or spatial nature or both. The following are the some advantages of novel drug delivery system: Controlled administration of therapeutic dose at desirable delivery rate, maximization of efficiency dose relationship, reduction of adverse side effects and enhancement of patient compliance. The novel drug delivery system should possess two characteristics: One is the delivery of drug at a determined rate and second is the release of the drug at the site of action. There are different types of pharmaceutical carriers are present.1 They are particulate type carrier ( particles), microspheres, nanoparticles, polymeric micelles and vesicular system (, transferosomes, pharmacosomes, ethosomes, niosomes etc.).2,3,4,5 Nowadays vesicles as a carrier system have been become the vehicle of choice for the drug delivery and lipid vesicles were found to be of value in immunology, membrane biology and diagnostic technique and most recently in genetic engineering.6

Vesicular systems The vesicular systems are highly ordered assembles of one are concentric lipid bilayer formed when certain amphiphilic building blocks are confronted with water. These biological vesicles origin was first reported in 1965 by Bingham. The lipid vesicles are rationalized for topical application since,7 • The , because of their lipophilic nature may serve as organic phase for poorly aqueous soluble substances.7 • They can be targeted intracellular and due to lipophilic nature, it acts as penetration enhancer.8 • Vesicular drug delivery reduces the cost of therapy by improved bioavailability of medication. • These carriers play an increasing important role in drug delivery because of the reduction in drug release rate; it is possible to reduce the toxicity of drug case of poorly soluble drugs. They can incorporate both by hydrophilic and lipophilic drugs. • Prolong the existence of the drug in systemic circulation and reduces the toxicity. Delays elimination of rapidly metabolized drugs and thus function as sustained release systems.9

Types of vesicular drug delivery carriers7 There are different types of vesicular drug delivery system. They are as follows: Liposomes: Liposomes are simple microscopic vesicles in which an aqueous volume is entirely enclosed by a membrane composed of a lipid molecule. These are the most widely known vesicular delivery system. The assembly into closed bilayered structures is a spontaneous process and usually needs some input of energy in the form of physical agitation, sonication, heat etc. The lipid soluble or lipophilic drugs get entrapped within the bilayered membrane, whereas water soluble or hydrophilic drugs get entrapped in the central aqueous core of the vesicles. It has wide advantages of biodegradability, moisturizing, restoring action and sustained dermal release. 10

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Pharmacosomes: “Pharmakon” means linking a drug and “soma” means carrier. They are the colloidal dispersions of drug covalently bound to lipids. Pharmacosomes are amphiphilic lipid vesicular system containing phospholipids complex which reduces interfacial tension and at higher concentration exhibit mesomorphic behaviour. Any drug possessing an active hydrogen atom (-

COOH,-OH,-NH2 etc.) can be esterified to the lipid with or without spacer chain that strongly result in an amphiphilic compound which will facilitate membrane, tissue or cell wall transfer in the organism. It improves bioavailability of poorly water soluble drug as well as poorly lipophilic drug.11

Transferosomes: Transferosomes are vesicles composed of phospholipids with surfactant and ethanol as well as ultradeformable vesicle possessing an aqueous core surrounded by the complex lipid bilayer. Higher membrane hydrophilicity and flexibility of transferosomes tend to avoid aggregation and fusion. Transferosomes was introduced for the effective transdermal delivery of number of low and high molecular weight drugs.12 It can penetrate the intact stratum corneum spontaneously along two routes in the intracellular lipid that differ in their bilayers properties. It consists of both hydrophilic and hydrophobic properties; high deformability gives better penetration of intact vesicles.13

Ethosomes: Ethosomes are lipid vesicles containing phospholipids, alcohol (ethanol and isopropyl alcohol) in high concentration and water. These are the slight modification of well established drug carrier liposomes. Ethosomes are noninvasive delivery carriers that enable drugs to reach the deep skin layers and or the systemic circulation. Unlike classic liposomes, that are known mainly to deliver drugs to the outer layers of skin, Ethosomes can permeate through the stratum corneum barrier.14 It can entrap drug molecules with various physicochemical characteristics like hydrophilic, lipophilic or amphiphilic.

Niosomes: Niosomes are non-ionic surfactant vesicles obtained on hydration of synthetic non-ionic surfactants with or without incorporation of cholesterol or other lipids. The vesicle is composed of a bilayer of non-ionic surface active agents and hence, it was named as niosomes.15 Niosomes have recently been shown to greatly increase transdermal drug delivery and also can be used in targeted drug delivery. They improve oral bioavailability of poorly absorbed drugs and enhance skin penetration.16

Vesosomes: Bilayer compartments led to the development of a multicompartment structure of unilamellar vesicles trapped within an exterior membrane called vesosome. The inner compartments of the vesosome can encapsulate multiple drugs or have different bilayer compositions to optimize release.17

Phytosomes: Phytosomes are complexes between a pure phospholipid and pure active principles from the chemical perspective. Phytosomes are developed to incorporate standardized plant extract or water soluble phytoconstituents into phospholipids to produce lipid compatible molecular complexes called phytosomes.18,19

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Table No.1 List of drug Available in lipid vesicular delivery system

Drug Carrier

Insulin Liposomes Didanosine Pharmacosomes Acyclovir Pindolol maleate Pharmacosomes Bupranolol HCl Norgesterol Transferosomes Tamoxifen Interferon α Transferosomes nterleukin Doxorubicin Niosomes Methotrexate Pentoxifylline Niosomes

Diclofenac Minoxidil Ethosomes Testosterone

Sphingosomes: These are concentric, bilayered vesicle in which an aqueous volume is entirely enclosed by a membranous lipid bilayer mainly composed of natural or synthetic sphingolipid.20 Liposomal phospholipid can either undergo chemical degradation such as oxidation and hydrolysis or as a result of these changes, liposome maintained in aqueous suspension may aggregrate, fuse or leak their content. The hydrolysis may be avoided altogether by use of lipid which contains ether or amide linkage instead of ester linkage (Sphingolipid) or phospholipid derivatives with the 2-ester linkage replaced by carbomoyloxy function.7 Sphingosomes may be administered orally or transderamlly. In simple way we can say sphingosome is liposome which is composed of sphingolipid.

Aquasomes: Drugs are allowed to adsorb on the surface of nanoparticles in the presence of carbohydrate film that prevents soft drugs from changing the shape and being damaged when surface bound.20 These carbohydrate stabilized nanoparticles of ceramics or calcium phosphate are known as aquasomes. Aquasomes are like “bodies of water” and their water like properties help to protect and preserve the fragile biological molecules.21 It is comprised of a solid phase nanocrystalline core coated with oligomeric film to which the drug moieties or biochemically active molecules are absorbed with or without modification. These three layered structures are self-assembled by non- covalent and ionic bonds.

Virosomes: Virosomes are virus-like spherical particles with a mean diameter of 120-180 nm, consisting of reconsitituted influenza virus envelopes, lacking the genetic material of the native virus. Virosomes are produced from influenza virus through a detergent solubilisation and removal procedure. Properly reconstituted virosomes retain the cell binding and membrane fusion properties of the native virus, mediated by the viral envelope glycoprotein haemagglutinin. Virosomes act both

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as a carrier and as an adjuvant, with multiple functions during the induction of an immune response.22

Colloidosomes: It is a novel class of microcapsules whose shell consists of coagulated or fused colloid particles at interface of emulsion droplets. The particles self assemble on the surface of droplets in order to minimize the total interfacial energy forming colloidosomes.23

Proliposomes: Proliposomes are composed of water soluble porous powder as a carrier upon which one may load phospholipids and drugs dissolved in organic solvent. Proliposomes can be stored sterilized in a dry state and dispersed or dissolved to form an isotonic multilamellar liposomal suspension by addition of water.24 MERITS 1. Suitable for both hydrophilic and lipophilic drugs. 2. The surfactants are biodegradable, biocompatible and non-immunogenic hence can be used safely in the preparation. Handling and storage of surfactants requires no special conditions. 3. Liposomes could encapsulate not only small molecules but also macromolecules. 4. Liposomes reduce the toxicity and increased stability of entrapped drug via encapsulation. It alters the pharmacokinetic and pharmacodynamic property of drugs like reduced elimination, increased circulation life time. 5. Liposomes help to reduce exposure of sensitive tissues to toxic drugs.7 6. In pharmacosomes, the drug is covalently bound hence membrane fluidity has no effect on the release rate. 7. Pharmacosomes depends upon the phase-transition temperature of the drug-lipid complex; as a result there is no leakage of drug take place.7 8. Transferosomes possess an infrastructure consisting of hydrophilic and hydrophobic moieties together and as a result can accommodate drug molecules with wide range of solubility. 9. Transferosomes possess high entrapment efficiency, incase of lipophilic drug near to 90%.7 10. Sphingosomes provide selective passive targeting to tumor tissue and through encapsulation increases the stability and improve pharmacokinetic effect.9 11. Ethosomes enhances permeation of drug through skin for transdermal drug delivery system. 12. Ethosomal system is passive, non-invasive and is available for immediate commercialization.14 13. Niosomes improve the therapeutic performance of the drug molecules by delayed clearance from the circulation protecting the drug from biological environment and restricting effects to target cells. 14. The vesicles may act as a depot, releasing the drug in a controlled manner. They are osmotically active and stable, as well as they increase the stability of entrapped drug. 15. They can be made to reach the site of action by oral, parenteral as well as topical routes. 16. The characteristics of the vesicle formulation are variable and controllable. Altering vesicle composition, size, lamellarity, tapped volume, surface charge and concentration can control the vesicle characterisitics.16 17. Phytosomes enhances the lipid insoluble polar phytoconstituents through oral and topical route and has better stability by the formation of chemical bonds between the phosphatidyl choline and phytoconsituent.18,19

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18. Virosomes enables drug delivery into the cytoplasm of target cell, promotes fusion activity in the endolysosomal pathway. 19. Virosomes extends the uptake, distribution and elimination of drug in body. It has no disease transmission risk and auto immunogenity or anaphylaxis.22 20. Colloidosomes membrane offer great potential in controlling the permeability of the entrapped species and allow the selective and time release. 21. Colloidosomes control the mechanical strength allows the yield stress to be adjusted to withstand varying of mechanical loads and to enable release by defined shear rates.23

APPLICATION 1. Sphingosomes used in tumor therapy, drug delivery vehicles, ophthalmic drug delivery, gene delivery, immobilization, immunology and in cosmetic industry.9 2. Ethosomes can be used for transdermal delivery of hydrophilic and impermeable drugs through the skin and used in the treatment of baldness, parkinson’s disease, diabetes, candidiasis and psoriasis.14 3. Niosomes used mainly in targeting of bioactive agents, in the treatment of neoplasia and leishmainiasis and used as a carrier for haemoglobin and delivery of peptide drugs. 4. Phytosomes are used as liver protectant (Silybum marianum). 5. Phytosomes can be used in the anti-inflammatory activity as well as in pharmaceutical and cosmetic compositions.18 6. Aquasomes are used as a carrier for delivery of vaccines, haemoglobin, drugs, dyes, and genetic material.21 7. Colloidosomes used in the antimicrobial, antifungal and antiviral therapy and also in the brain delivery, ocular delivery, DNA delivery and in the enzyme immbolization. 8. Colloidosomes used as drug or protein delivery carrier and in the encapsulation of enzymes, tumour therapy, cosmetics and dermatology.23 9. Liposome are potential carrier for controlled drug release of tumours therapeutic agents and antibiotic, for gene and antisense therapy through nucleic acid sequence delivery, immunization through antigen delivery and for anti-parkinsons. 10. Liposomes also used in the non medical areas like bioreactors, catalysts, cosmetics and ecology.25 11. Multiple compartments of the vesosomes give better protection to the interior contents in the serum.26 12. Transferosomes used as a carrier for the transport of protein, peptides and interferons.27 13. Virosomes are used in the gene delivery, DNA or RNA delivery and for the activation of murine lymphocyte and in the cancer treatment.28

FORMULATION APPROACHES The method of preparation of vesicular drug delivery system depends upon their size, size distribution and entrapment efficiency of the aqueous phase and membrane permeability of the vesicles.

• Sonication Phospholipid is dispersed in water by heating at 400 until a colloidal dispersion is obtained. Ethanol is mixed with propylene glycol at same temperature in separate vessel and added

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to above prepared aqueous phase. The mixture is probe sonicated at 60 for 3 minutes using a sonicator with a titanium probe to yield vesicles.15

• Detergent solubilisation Mostly influenza virus envelope is used to produce virosomes and this virosomes are solubilised using detergent (octagluoside, triton x-100, nonidert p-40). Due to solubilisation with detergent internal viral protein and genetic material will sediment then detergent is removed by different method such as dialysis and hydrophobic resins from supernatant. Then using ultracentrifugation process viral matrix protein and nucleiocapsid is removed. Protein obtained in supernatant represents viral envelope protein only. Now antigen such as parasite, carcinogenic cell, bacterium or whole cell which is already coupled to lipid anchor is mixed with polymer or surfactant and this solution is processed with virosome carrier so that antigen bound virosome is obtained. Virosome can be made from Epstein-burr, Sindbis,semliki-foest virus, Friend murine leukemia virus, Herpes simplex virus and Newcastle disease virus.22

• Slow spraying coating method In this method, the surfactant is added to an organic solvent and sprayed onto carrier. Then the solvent is evaporated. This process is repeated until the desired surfactant loading is achieved, because the carrier is soluble in the organic solvent. As the carrier dissolved, hydration of this coating allows the formation of multilamellar vesicles.24

• Co-acervation phase separation method In this method, surfactant, lipid and drug are taken in a wide mouthed glass vial and small amount of alcohol is added to it. All the ingredients are mixed well and warmed over water bath at 60-70 for 5 min until the surfactant mixture is dissolved completely. Then the aqueous phase is added to the above vial and warmed still a clear solution is formed which is then converted into proniosome gel on cooling.24

• The bubble method It is novel technique which has recently developed method and allows the penetration of liposomes and niosomes without the use of organic solvents. The bubbling unit consists of round bottom flask with three necks positioned in water bath to control the temperature. Water cooled reflux and thermometer is positioned in first and second neck respectively and nitrogen is supplied through the third neck. Cholesterol and surfactant are dispersed together in this buffer (pH 7.4) at 70 , the dispersion mixed for 15 seconds with high shear homogenizer and immediately afterwards “bubbled” at 70 using nitrogen gas.8,15,29 • Ether injection method The surfactant is dissolved in diethyl ether into warm water maintained at 60. The surfactant mixture in ether is injected through 14-gauge needle into an aqueous solution of material. Vaporization of ether leads to formation of vesicles.29 • Thin film hydration techniques Vesicle forming ingredients such as surfactant, cholesterol, and lecithin are dissolved in a volatile organic solvent (diethyl ether, chloroform or methanol) in a round bottom flask. The organic solvent

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is removed at room temperature using rotary evaporator leaving a thin layer of solid mixture deposited on flask wall and dried film can be rehydrated which forms typical multilamellar vesicles.29,30

• Trans membrane pH gradient (inside acidic) drug uptake process (remote loading) In this method, a solution of surfactant and cholesterol is made in chloroform. The solvent is then evaporated under reduced pressure to get a thin film on the wall of the round bottom flask. The film is hydrated with 300 ml of citric acid at pH 4 by vortex mixing. The resulting multilamellar vesicles are frozen and thawed 3 times and later sonicated. To the niosomal suspension, aqueous solution containing 10 mg/ml of drug is added and vortexed. The pH of the sample is then raised to 7.0-7.2 using 1M disodium phosphate. This mixture is later heated at 60 for 10 min to yield niosomes.29

• Micro fluidization Micro fluidization is a recent technique used to prepare unilamellar vesicles of defined size distribution. This method is based on submerged jet principle in which two fluidized streams interact at ultra high velocities, in precisely defined micro channels within the interaction chamber. The impingement of thin liquid sheet along a common front is arranged such that the energy supplied to the system remains within the area of vesicles formation.29

• Reverse phase evaporation technique This method involves the creation of the solution of cholesterol and surfactant (1:1) in a mixture of ether and chloroform. An aqueous phase containing drug is added to this solution and the resulting two phases are sonicated at 4-5. The clear gel is formed further sonicated after the addition of a small amount of phosphate buffered saline (PBS). The organic phase is removed at 40 under low pressure. The resulting viscous suspension is dilute with PBS and heated on a water bath at 60 for 10 min to yield noisome. 29

• Thin film hydration techniques Vesicle forming ingredients such as surfactant, cholesterol, and lecithin are dissolved in a volatile organic solvent (diethyl ether, chloroform or methanol) in a round bottom flask. The organic solvent is removed at room temperature using rotary evaporator leaving a thin layer of solid mixture deposited on flask wall and dried film can be rehydrated which forms typical multilamellar vesicles.29,30

CHARACTERIZATION METHODS • Degree of deformability or Permeability measurement: The permeability study is one of the important and unique parameter for characterization. The deformability study is done against the pure water as standard. The preparation is passed through a large number of pores of known size micro porous filters with pore diameter between 50 nm and 400 nm, depending on the starting prepared suspension. Particle size and size distributions are noted after each pass by dynamic light scattering measurements.12, 13 • Vesicle shape: The shape of the vesicles can be determined by using transmission electron microscopy and by using scanning electron microscopy.14

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• Vesicle diameter: Their diameter can be determined using photon correlation spectroscopy, dynamic light scattering and freeze fracture electron microscopy. 14 • Surface tension measurement: The surface tension activity of the drug in an aqueous solution can be measured by the Du Nouy ring tensiometer.14 • Surface electric potential and pH: The surface electric potential and pH can be determined by zeta potential measurement and pH probes.23 • Separation of free (unentrapped) drug: The unentrapped drug can be separated from entrapped drug using techniques like centrifugation, by using cellophane dialysis tubing D-9777 and dialyzing against 400 ml. saline at 4 for 24 hours.24 • Permeation studies in skin: The misinterpretation in conventional light microscopy and electron microscopy can be minimized by confocal scanning laser microscopy.27 • Invitro drug release: The release rate study includes the use of dialysis tubing and performed for determining the permeation rate. A dialysis sac is washed and soaked in distilled water and then the prepared vesicle is pipette out into a bag and placed in 200 ml buffer solution in 250 ml beaker with constant stirring at 25 37. At various time intervals, the buffer is analysed for the drug content which is released by either an appropriate assay method or using UV spectrophotometer and can be quantified by a modified HPLC method.31 • Drug entrapment: After preparing vesicular dispersion, the drug which is entrapped can be separated by dialysis55,ultracentrifugation,59 or gel filtration.60 The drug remained entrapped is determined by disrupting the vesicles using 0.1% Triton X-100 or 50% n-propanol. 24,29,31 100

CONCLUSION Vesicular systems have been investigated as a major drug delivery system due to their flexibility to be tailored for various purposes. Vesicular drug delivery system still now plays an important role in drug targeting and controlled release of the drug. Current research trends are based on different approaches for cellular targeting. The relatively new and existing data shows that we can explore the vesicular system for the forthcoming market. Thus, this novel technique has got a great potential for overcoming current problems faced by the conventional techniques.

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